Heart disease or heart failure following myocardial infarction is still the major cause of death in the western world. The mature heart muscle (myocardium) cells of mammals are those that reach their last stage of differentiation and, therefore, are considered unable to undergo proliferation (see P. P Rumynastev, Growth and Hyperplasia of Cardiac Muscle Cells, B. M. Carlson, ed., Harwood, New York, 1991, pp. 3-68). Thus, the myocardium may be afflicted with hypertrophy (increase in cell mass and not cell number) due to mechanical stress or ischemia (inadequate oxygen supply to the cells). Following ischemia, due to occlusion of blood supply to the cells during myocardial infarction (MI), irreversible, physiological changes occur in the cells, which degenerate and are replaced by non-contracting scar tissue (infarcted zone) with time (see M. C. Fishbein, M. B. McLean et al., Experimental myocardial infarction in the rat, Am. J. Pathol. 90: 57-70, 1978).
In particular, cells of the myocardium traumatized by ischemia enter a toxic ischemic cascade resulting in a number of damaging processes to the cells, such as membrane breakdown, mitochondrial disruption, enhanced proteolysis, etc., mainly as the result of unbalanced rates of energy production and consumption. Under conditions of poor oxygen availability, an anaerobic glycolytic pathway replaces the aerobic metabolism as the primary source of adenosine triphosphate (ATP), facilitating cell survival. The anaerobic glycolytic metabolism and related anaerobic cell survival, however, is a short-lived mechanism, as this natural up-regulation of glycosis is stopped by the accumulation of lactate, which inhibits the key glycolytic enzyme phosphofructokinase (PFK) (see E. Hofmann, The significance of phosphofructokinase to the regulation of carbohydrate metabolism, Rev. Physiol. Biochem. Pharmacol. 75: 2-68, 1976).
Current clinical treatments of acute MI include thrombolytic treatment (W. Ganz, N. Buchbinder, H. Marcus et al., Intracoronary thrombolysis involving myocardial infarction, Am. Heart 101: 4-10, 1983); PTCA (coronary angioplasty) performed on occluded arteries (A. R. Gruentzig et al., Long-term follow-up after percutaneous transmural coronary angioplasty, N. Engl. J. Med. 316: 1127-32, 1987); and also bypass surgery as near as possible to the occurrence of the MI (G. M. Fitzgibon, A. J. Leach, H. P. Kafka et al., Coronary bypass graft fate: long-term angiographic study, J. Am. Colo. Cardiol. 17: 1075-80, 1991). These procedures are expensive, demand very highly qualified personnel and physicians, and are not always practically possible in health care. Moreover, these methods endeavor to alter the consequences of the irreversible ischemic injury that occurs in the cells rather than inhibit such consequences. It should be mentioned that even with qualified personnel and first-rate treatment, the above procedures are not always successful.
Several attempts have been made in the past to reduce the infarcted area in the myocardium following induction of MI in experimental animals. These include the use of corticosteroids, various antioxidant agents, and chemical agents for prolonging anaerobic cell survival.
Exogenous fructose-1,6-diphosphate (FDP) was found to bypass the PFK block and restore anaerobic ATP and creatine phosphate (CP) production (see A. K. Markov, N. C. Oglethorpe, et al., Hemodynamic electrocardiographic and metabolic effects of fructose diphosphate on acute myocardial ischemia, Am. Heart J. 100: 639-646, 1980). In experiments performed on animals, FDP was found to improve hemodynamic parameters, reduce arrhythmias and infarct size, and increase survival rate. (See A. K. Markov, N. C. Oglethorpe, et al., op. cit., and J. W. Starnes, K. S. Seiler, et al., Fructose-1,6-diphosphate improves efficiency of work in isolated perfused rat heart, Am. J. Physiol. 262: M380-M384, 1992. All of these articles are incorporated herein by reference.)
Ischemic cardiac tissues may have their blood supply restored, using various treatments known in the art, such as coronary angioplasty. In the course of such a treatment, the ischemic tissue may be rapidly reperfused with blood. Such rapid reperfusion has been shown, at least in some cases, to result in post-reperfusion injury, i.e., damage induced by the reperfusion per se. The injury may be caused, inter alia, by superoxides formed within the tissue due to a sharp increase in oxygen supply following the reperfusion procedure. Superoxides are highly-reactive, toxic free radical substances, which undergo detrimental, undesirable reactions with organic and inorganic cellular substances. Indigenous and/or exogenous antioxidants alleviate the toxic effect of the superoxides by either preventing their formation or scavenging the free radicals immediately upon formation. Use of exogenous free radicals scavengers for alleviation of post-reperfusion injury in heart muscle has recently been reported (see E. P. Chen et al., Extracellular superoxide dismutase transgene overexpression preserves post-ischemic myocardial function in isolated murine hearts, Circulation, 94:412-417, 1996, which is incorporated herein by reference). In particular, non-toxic seleno-organic free radical scavengers were found to exhibit such a cytoprotective effect (see V. Ullrich, et al., Seleno-binding equilibria between plasma and target proteins, Biochem. Pharmacol. 52:15, 1996, which is incorporated herein by reference).
Implantation of cells from skeletal muscle origin or of embryonic heart muscle cells (cardiomyocytes) into ischemic or infarcted regions of the heart has recently been reported (see R. K. Li et al., Cardiomyocyte transplantation improves heart function, Ann. Thorac. Surg. 62:454-460, 1996, which is incorporated herein by reference). The implanted cells survived the implantation and remained viable for a period of at least several weeks thereafter. The cells, implanted into a cold injury site of the left ventricle myocardium of rats, were reported to significantly improve the heart function (with respect to various physiological parameters) in comparison with control rats, which had not undergone cells implantation. In experiments on mice performed (see J. E. Morgan et al., Yield of normal muscle from precursor cells implanted into preirradiated and nonirradiated legs of young and old max mice, Muscle & Nerve 19:132-139, 1996, which is incorporated herein by reference), only about 10% of the implanted cells of skeletal muscle origin survived the implantation and remained viable for a period of few weeks after the implantation.
Low power laser irradiation has recently been found to modulate various processes in different biological systems (see M. Belkin, B. Zaturunsky, and M. Schwartz, A critical review of low power laser bioeffects, Laser Light Ophthalmol. 2: 63-71, 1988, and T. Karu, Photobiology of low power laser effects, Health Phys. 56: 691-704, 1988). For example, in isolated mitochondria, He—Ne laser irradiation (5 J/cm2) elevated membrane potential and production of ATP, while in isolated fibroblasts with the same radiation, an increase in collagen production was observed. The effect of low power laser irradiation on regeneration processes following trauma has thus far been investigated in the skin, the peripheral nervous systems, skeletal muscles and bone. It has been found that laser irradiation given at the right time and energy level modulates the process of skeletal muscle regeneration and, in most systems, causes a faster recovery after trauma and an enhanced rate of regeneration in muscles and bone (see N. Weiss and U. Oron, Enhancement of muscle regeneration in the rat gastrocnemius muscle by low power laser irradiation, Anat. Embryol. 186: 497-503, 1992, and O. Barushka, T. Yaakobi and U. Oron, Effect of laser irradiation on the process of bone repair in the rat tibia, Bone 16: 47-55, 1995). Low power laser irradiation has also been found to induce a twofold increase in new blood vessels formation (i.e., angiogenesis) in the injured zone of skeletal muscles (see A. Bibikova, N. Belkin and U. Oron, Enhancement of angiogenesis in regenerating gastrocnemius muscle of the toad by low energy laser irradiation, Anal Embryol. 190:597-602, 1994, which is incorporated herein by reference).
In a recent study, the effect of irradiation of the blood (subclavian artery) by He—Ne lasers in patients after MI was observed (see N. N. Kipshidze et al., Intravascular laser therapy of acute myocardial infarction, Angiology 801-808, September 1990, which is incorporated herein by reference). The study reports a better recovery of the laser-irradiated patients in terms of the levels of enzyme activity (creatine phosphokinase) in blood (which was lower in the irradiated patients) and a reduction of arrhythmia of the heart.
It is to be emphasized that the Kipshidze et al. paper does not teach biostimulation of the myocardium itself but rather of the blood. The authors write in the Abstract “A new method for . . . using monochromatic He—Ne laser . . . this paper deals with the effect of endovascular (inside blood vessels) laser blood irradiation on high-grade arrhythmias”. On page 802, lines 2-3, it states that “Endovascular laser therapy was performed using an LG-75 laser via an optical light guide introduced into the lumen of the superior vena cava . . . ”. Thus, the myocardium was not irradiated but rather the blood.
It is known in the art (see Mester, A. R., Modalities of low power laser applications, Galletti et al. (eds.) Laser Applications in Medicine and Surgery, Monduzzi Editore (1992), pp. 33-40) that the energy emitted from a He—Ne laser, even with high power, is absorbed by hemoglobin in the red blood cells and by living tissues. This type of energy at the specific wavelength (632.2 nm) does not penetrate well through living tissues. The loss in power output is about 90% after 2 mm depth of tissue and there is practically no power capable of penetrating beyond 3 mm depth of tissue with a moderate blood supply. It is also acknowledged in the art that exposure of the tissue to power less than 4 mW has no biostimulatory effect on tissues (see Galletti et al. ibid. and Bradley, P. F. and B. Gursoy, Penetration studies of low intensity laser therapy (LILT) wavelength, Proc. WALT 1996, p. 18.).
Thus, when energy from the He—Ne laser source (the power level is not cited in the Kipshidze et al. work, but can be at most 40 mW) is conveyed through an optical fiber (which causes a loss of approximately 30-40% of the source), it ends up at the tip of an optical fiber at no more than 25 mW. Since the tip is situated in a blood vessel (superior vena cava) which is at least 5 cm in distance from the heart muscle, the energy which is absorbed by the heart muscle from the optical fiber is practically zero and has no biostimulatory effect on the heart muscle based on the above scientific knowledge.
Other studies have reported qualitative alternations in the ultrastructure of musculature (see Ruzov, I. V. and Baltrushaitis, K. S., Ultrastructural changes in the myocardium under the action of the helium-neon laser and obzidan, Vopr. Kurotol. Fizioter. Lech. Fiz. Kult. 5-6: 62-4, 1992), blood vessels (see Ruzov, I. V. and Baltrushaitis, K. S., The microcirculatory bed of the ischemic myocardium under the combined action of a low-intensity helium-neon laser and finoptin, Vopr. Kurotol. Fizioter. Lech. Fiz. Kult. 4: 31-3, 1993) and mitochondria of the myocardium of rabbits in a hypodynamic stage following irradiation of the blood by He—Ne laser (see Ruzov, I. V. and Rishkus, L. A., The effect of the helium-neon laser on the cyclic nucleotide level in experimental hypodynamia, Vopr. Kurotol. Fizioter. Lech. Fiz. Kult. 2:51-53, 1992). The irradiation in the above studies was performed by insertion of fiber optics through the ear vein in the ear of the rabbits. It should be emphasized that in the Russian Republic, irradiation of blood by UV or low power lasers is a common procedure towards a better recovery in many human illnesses (see Ruzov, I. V. A comparative study of the action of the helium-neon laser, perlinganite and heparin on the energy apparatus of the ischemic myocardium. Vopr. Lech. Fizioter. Lech. Fiz. Kult. 5-6: 62-4, 1994).
In the four aforementioned scientific papers by Ruzov et al., the authors use an experimental system of He—Ne laser at a power level of 1.5 mW, similar to Kipshidze et al. Again, the energy was introduced by fiberoptics into a vein in the ear of a rabbit. As mentioned above with reference to the paper by Kipshidze et al., the energy that is finally transmitted from the vein in the ear to the heart muscle is practically zero, without any expected biostimulatory effects on ischemic or hypodynamic heart muscle, as mentioned in these scientific papers.
Russian Patent 1715351 to Golikov et al., relates to irradiation treatment by a He—Ne laser at acupuncture points to help recovery of heart disease in the post-infarction period. However, this patent can not relate to irradiation of the myocardium because the He—Ne laser beam, even if aimed at points on the chest of a human patient above the heart, cannot penetrate more than 2-3 mm. Thus, practically no laser energy can reach the heart muscle since the muscle between the ribs in humans is at least 3 cm thick. The positive effects achieved in laser irradiated patients, is perhaps due to acupuncture treatment or reflexogenic therapy, as cited by the authors themselves in the last paragraph of the patent.
Russian patent 1806781 to Leveshunov et al., deals with magnetic-laser treatment to improve clinical prognosis of patients with complicated acute myocardial infarction. Pulsed laser irradiation and infrared radiation (wavelength not mentioned) are applied to the patients' chest wall. There is no known data in the art on the bioeffects of combination of magnetic field and laser irradiation on tissues The pulsed laser, as suggested in this patent, has a mean power of 12 mW, while the continuous infrared radiation has a power of 50 mW. However, the laser beam has to penetrate through the chest skin and muscles between the ribs with a total average tissue width of about 3 to 5 cm before reaching the heart muscle. Since the laser power diminishes within living tissue in an exponential manner with respect to depth, the maximal laser power output incident on the heart, as suggested by Leveshunov et al., will be reduced through the thick chest wall of a patient to a practically zero, obviously too low to cause any stimulatory effect on the heart muscle.